Biology of the P53 Protein

描述（由申请人提供）：1型胰岛素样生长因子受体（IGF-IR）最近因其在正常和异常细胞生长中的可能作用而成为工业界最喜欢的靶点之一。IGF-IR信号在长寿中也起着重要作用，来自C。从优雅到优雅IGF轴以非冗余的方式控制动物和培养细胞中约50%的生长，主要是通过激活其对接蛋白，胰岛素受体底物-1（IRS-1）。IRS-1（或其在果蝇中的同源物）的缺失导致动物或细胞的大小约为50%。我们最近发现IRS-1易位到细胞核，在那里它结合并激活UBF 1（上游结合因子1），UBF 1是一种调节RNA聚合酶I活性的蛋白质，因此调节细胞（和身体）的大小。在本研究中，我们拟研究：1）IRS-1调节UBF 1活性和/或稳定性的机制，2）核IRS-1与其它核仁蛋白竞争激活核糖体DNA启动子的机制，3）核IRS-1与其它核仁蛋白竞争激活核糖体DNA启动子的机制，4）核IRS-1与其它核仁蛋白竞争激活核糖体DNA启动子的机制，5）核IRS-1与其它核仁蛋白竞争激活核糖体DNA启动子的机制。和3）IRS-1与细胞核中的SV 40 T抗原和选择的RNA聚合酶-2指导的启动子的物理和生物学相互作用，这种相互作用可能对细胞的转化至关重要。这些研究对我们的癌症生物学基础知识有直接影响，并可能揭示衰老的机制。

DESCRIPTION (provided by applicant): The type 1 insulin-like growth factor receptor (IGF-IR) has recently become one of the favorite targets of industry for its possible role in the growth of normal and abnormal cells. IGF-IR signaling also plays a significant role in longevity, from C. elegans to mammalians. The IGF axis controls, in a non-redundant way, about 50% of growth in animals and cells in culture, largely through the activation of its docking protein, the insulin receptor substrate-1 (IRS-1). Deletion of IRS-1 (or its homologues in Drosophila) results in animals or cells that are roughly 50% in size. We have recently found that IRS-1 translocates to the nuclei where it binds and activates UBF1 (Upstream Binding Factor 1), a protein that regulates RNA polymerase I activity, and therefore cell (and body) size. In this application, we propose to study: 1) the mechanism by which IRS-1 regulates the activity and/or the stability of UBF1; 2) the mechanism(s) by which nuclear IRS-1 competes with other nucleolar proteins for the activation of the ribosomal DNA promoter; and 3) the physical and biological interactions of IRS-1 with the SV40 T antigen and selected RNA polymerase-2-directed promoters n the nuclei of cells, an interaction that may be critical for the transformation of cells. These studies have a direct impact on our basic knowledge of the biology of cancer and may throw light on mechanisms of aging.